The goal of this project is to elucidate how autophagy regulates the onset and progression of salivary gland tumors, and how the pathway interacts with oncogenic signaling pathways during tumorigenesis. Salivary gland tumors are both rare and highly varied. Because of their rarity, previous investigation of salivary cancer is limited an as yet, there are no useful mouse models of salivary gland cancer available that resemble the pathophysiology of human salivary cancers. Consequently, therapeutic options for salivary tumors are limited, personalized treatment is virtually non-existent and there is a glaring lack of pre-clinical and clinical validation. Autophagy is a catabolic process that uses the cell's lysosomal system to degrade its own components including cytoplasmic organelles and proteins. In the last decade, it has been established that autophagy plays important and complicated roles in the onset and progression of tumors via multiple mechanisms. It is therefore a promising therapeutic target and nearly 20 clinical trials targeting autophagy are in progress. Although autophagy promotes tumor progression in later stages, it plays a tumor-suppressive role early during tumorigenesis. Therefore it is crucial to determine the precise role of autophagy at different stages of salivary tumor development for future autophagy-based therapeutics. The role of autophagy is not well studied in salivary tumors, but our preliminary data, together with published reports, indicate that autophagy plays a dual role. It reduces genetic instability early during tumorigenesis to suppress tumor formation, but then shifts its rol to provide a survival advantage for established tumors experiencing endogenous and exogenous metabolic stresses. We hypothesize that autophagy suppresses tumor initiation by inhibiting the formation of tumor-initiating cells, but acts as a key metabolic pathway for the survival of advanced salivary tumors. We will determine the role autophagy plays in suppressing submandibular tumorigenesis using a mouse model that contains a K-RasG12V transgene. The K-RasG12V can be activated to specifically induce tumors in submandibular tissue, using a Cre-recombinase that is induced by tamoxifen-feeding. We will knock-out Atg5, an essential gene for autophagy, to impair autophagy in the K-RasG12V background. Using nucleotide labeling to trace cell lineages, we will compare specific sub-populations of salivary tumor cells from autophagy- competent and autophagy-impaired K-RasG12V transgenic mice. The novel transgenic mouse model developed for this proposal will not only assist us in understanding the role of autophagy in regulating salivary tumorigenesis, but will also be invaluable as tools to screen for, and identify, novel therapeutic targets to treat these rare, but deadly cancers. Furthermore, the new knowledge will have potential relevance to the role of autophagy in regulating other oncogenic Ras-induced cancers.